Abstract
Endogenous steroid hormones, especially glucocorticoids and mineralocorticoids, derive from the adrenal cortex, and drastic or sustained changes in their circulatory levels affect multiple organ systems. Although hypoxia signaling in steroidogenesis has been suggested, knowledge on the true impact of the HIFs (Hypoxia-Inducible Factors) in the adrenocortical cells of vertebrates is scant. By creating a unique set of transgenic mouse lines, we reveal a prominent role for HIF1α in the synthesis of virtually all steroids in vivo. Specifically, mice deficient in HIF1α in adrenocortical cells displayed enhanced levels of enzymes responsible for steroidogenesis and a cognate increase in circulatory steroid levels. These changes resulted in cytokine alterations and changes in the profile of circulatory mature hematopoietic cells. Conversely, HIF1α overexpression resulted in the opposite phenotype of insufficient steroid production due to impaired transcription of necessary enzymes. Based on these results, we propose HIF1α to be a vital regulator of steroidogenesis as its modulation in adrenocortical cells dramatically impacts hormone synthesis with systemic consequences. In addition, these mice can have potential clinical significances as they may serve as essential tools to understand the pathophysiology of hormone modulations in a number of diseases associated with metabolic syndrome, auto-immunity or even cancer.
Highlights
Steroidogenesis in the adrenal gland is a complex process of sequential enzymatic reactions that convert cholesterol into steroids, including mineralocorticoids and glucocorticoids [1]
We combined this creline to locally knock-out PHD2, the HIFα’s direct regulator, together with HIF1α; generating the Akr1b7:cre-Phd2/ Hif1ff/ff mouse line
QPCR analysis using mRNA from whole adrenal glands already revealed significant reduction of Hif1α, a clear tendency in reduced Phd2 expression and a substantial increase of Hif2α mRNA when compared to glands from WT littermates (Fig. 1b)
Summary
Steroidogenesis in the adrenal gland is a complex process of sequential enzymatic reactions that convert cholesterol into steroids, including mineralocorticoids and glucocorticoids [1]. As steroidogenesis is a tightly regulated process, proper control of adrenal cortex function relies on appropriate endocrine signaling, tissue integrity, and homeostasis [5]. Hypoxia-inducible factors (HIFs) are the main transcription factors that are central to cellular adaptation to hypoxia in virtually all cells of our body. Oxygen insufficiency renders these PHDs inactive, leading to the binding of the HIF-complex to hypoxia-responsive elements (HRE) in the promoter of multiple genes that ensure oxygen delivery and promote adaptive responses to hypoxia such as hematopoiesis, blood pressure regulation, and energy metabolism (reviewed in [11, 12]). Of the most intensively studied HIFα genes, HIF1α has a ubiquitous pattern of expression in all tissues, whereas expression of the paralogue HIF2α is restricted to a selection of cell types including endothelial cells,, liver hepatocytes, epithelial cells of the intestinal lumen, glia cells in the brain and renal erythropoietin-producing cells [15,16,17,18]
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